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Pierre-Alain Carrupt

Publications and source records attributed to Pierre-Alain Carrupt.

28 records · Page 2Linked to original sources
PubMed2003

Water-oil partition profiling of ionized drug molecules using cyclic voltammetry and a 96-well microfilter plate system.

PURPOSE: A new experimental set-up for studying partitioning of ionizable drugs at the interface between two immiscible electrolyte solutions (ITIES) by amperometry is presented. The method is quite general, as it can be applied to any charged drug molecule. METHODS: The procedure is based on 96-well microfilter plates with microporous filters to support 96 organic liquid membranes. The new methodology is first validated using a series of tetra-alkylammonium ions and subsequently used to construct the ion partition diagrams of 3,5-N,N-tetramethylaniline and 2,4-dinitrophenol. The lipophilicity of these drugs was examined by potentiometry and cyclic voltammetry in the NPOE/water system. RESULTS: Cyclic voltammetry resulted in potential-pH profiles of the studied drugs. When the aqueous phase pKa is already known, the logP(NPOE) of lipophilic drugs could be determined using a very little amount of solvents and drugs. The values of the partition coefficients for the neutral forms agree well with those obtained by potentiometry. CONCLUSIONS: The procedure based on commercially available 96-well microfilter plates is shown to be useful for determining logP of ionized drugs in a rapid and efficient way.

2,4-Dinitrophenol↗
PubMed2003

Synthesis and three-dimensional quantitative structure-activity relationship analysis of H3 receptor antagonists containing a neutral heterocyclic polar group.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H(3) receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.

Animals↗
PubMed2002

Lipophilicity and solvation of anionic drugs.

This paper first gives a brief review of the main techniques used to measure the lipophilicity of neutral and ionic drugs, namely the shake-flask method, potentiometry, and cyclic voltammetry at liquid-liquid interfaces. The lipophilicity of 28 acidic compounds with various functional groups was studied by potentiometry and cyclic voltammetry in the n-octanol/water and 1,2-dichloroethane/water systems in order to complement our understanding of the lipophilicity of neutral and ionized acids and to clarify the solvation mechanisms responsible for their partition. The parameter diff (log P(N-A)(dce)) (i.e., log P of the neutral acid minus standard log P of the conjugated anion in 1,2-dichloroethane/water) was shown to depend not only on intramolecular interactions and conformational effects in the neutral and anionic forms, but also on the delocalization of the negative charge in the anion, confirming the ability of Born's solvation model to describe qualitatively the effect of the molecular radius on the lipophilicity of ions.

Anions↗
PubMed2002

Exploration of the pharmacophore of 3-alkyl-5-arylimidazolidinediones as new CB(1) cannabinoid receptor ligands and potential antagonists: synthesis, lipophilicity, affinity, and molecular modeling.

A set of 29 3-alkyl 5-arylimidazolidinediones (hydantoins) with affinity for the human cannabinoid CB(1) receptor was studied for their lipophilicity and conformational properties in order to delineate a pharmacophore. These molecules constitute a new template for cannabinoid receptor recognition, since (a) their structure differs from that of classical cannabinoid ligands and (b) antagonism is the mechanism of action of at least three compounds (20, 21, and 23). Indeed, in the [(35)S]-GTP gamma S binding assay using rat cerebellum homogenates, they behave as antagonists without any inverse agonism component. Using a set of selected compounds, experimental lipophilicity was measured by RP-HPLC and calculated by a fragmental method (CLOGP) and a conformation-dependent method (CLIP based on the molecular lipophilicity potential). These approaches revealed two models which differentiate the binding mode of nonpolar and polar hydantoins and which could explain, at least for compounds 20, 21, and 23, the mechanism of action of this new family of cannabinoid ligands.

Animals↗
PubMed2002

Immobilized artificial membrane liquid chromatography: proposed guidelines for technical optimization of retention measurements.

The objectives of this study were to establish guidelines for the proper measurement of capacity factors (log k(IAMw) on immobilized artificial membrane (IAM) stationary phases. In this context, some aspects related to the extrapolation of log(kIAMw) values, the stability and properties of IAM.PC.DD2 stationary phases and the column-to-column variability are discussed. No significant difference was observed when using either acetonitrile or methanol for the linear extrapolation of log k(IAM) values. However, methanol seems more appropriate when working with ionized compounds. Plotting isocratic capacity factors against the percentage (v/v) of co-solvent instead of the mole fraction leads to more reliable log k(AMW) values. Furthermore, our results with a YMC ODS-AQ and an IAM.PC.DD2 HPLC column indicate that only small differences arise between extrapolated capacity factors when using the (w(w))pH or the (s(w))pH operational scale and correcting or not the ionic strength for dilution caused by the co-solvent. The use of the (s(w))pH scale is recommended when working with ionized compounds in order to avoid parabolic relationships during linear extrapolation. The pH-dependent retention of three ionizable drugs on an IAM.PC.DD2 phase showed that secondary interactions with the charged moieties of the chromatographic surface affect the retention of ionized compounds around physiological pH. Finally, it was shown that column ageing occurs also with IAM.PC.DD2 stationary phases and that it depends on the column as well as on the investigated analyte. The intra-batch variability for IAM.PC.DD2 phases was small, whereas a marked and solute-dependent batch-to-batch variability was apparent.

Chromatography, Liquid↗
PubMed2002

The relative partitioning of neutral and ionised compounds in sodium dodecyl sulfate micelles measured by micellar electrokinetic capillary chromatography.

The rational use of micelles in quantitative structure-activity and quantitative structure-permeation relationships implies a good knowledge of the nature of recognition forces underlying solute-micelle association. The aims of this study were to unravel the intermolecular interaction forces responsible for the association of neutral and ionised compounds with negatively charged sodium dodecyl sulfate (SDS) micelles, using micellar electrokinetic capillary chromatography (MEKC). The MEKC capacity factors (log k(MEKC)) of 36 neutral model solutes were analysed by linear solvation free-energy relationships (LSERs). The results indicate that the size and H-bond acceptor strength of solutes are mainly responsible for their MEKC retention. Compared to n-octanol, the SDS micelles are more cohesive and stronger H-bond donors. Strong attractive electrostatic interactions govern solute-micelle association for positively charged compounds and micelles of the opposite charge, whereas repulsive electrostatic interactions occur between negatively charged solutes and micelles of the same charge. The capacity factors measured for the ionised forms of the acids and bases under study (log k(MEKC)(I)) indeed lie on two distinct plateau, about -1.0 for the former and about 2.0 for the latter and depend on the solute's charge more than on its chemical structure. Thus, the derivation of a diff(log k(MEKC)(N-I)) value, defined as the difference between the log k(MEKC) values of the neutral and charged species, strongly correlates with the respective log k(MEKC)(N) value and does not afford additional information.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed2002

Molecular factors influencing retention on immobilized artifical membranes (IAM) compared to partitioning in liposomes and n-octanol.

PURPOSE: To assess the effect of molecular factors influencing retention on immobilized artificial membrane (IAM) high-performance liquid chromatography columns compared to liposomal partitioning and traditional n-octanol/water partition coefficients. METHODS: IAM capacity factors were measured at pH 7.0 on an IAM.PC.DD2 stationary phase. Liposomal partitioning at pH 7.0 and n-octanol/water partition coefficients were measured using the pH metric method. Partitioning in egg-phosphatidylcholine (PhC) liposomes was also measured by equilibrium dialysis for a series of beta-blockers. RESULTS: For the ionized beta-blockers, potentiometry and equilibrium dialysis yielded consistent partitioning data. For relatively large bases. IAM retention correlated well with PhC liposome partitioning, hydrophobic forces being mainly involved. For more hydrophilic compounds and for heterogeneous solutes, in contrast, the balance between electrostatic and hydrophobic interactions was not the same in the two systems. Hydrogen bonding, an important factor in liposomes partitioning, played only a minor role in IAM retention. CONCLUSIONS: Partitioning in immobilized artificial membranes depends on size, hydrophobicity, and charge. When hydrophobic interactions dominate retention, IAM capacity factors are well correlated with liposomal partitioning. On the contary, for hydrophilic solutes, the two systems do not yield the same information and are not interchangeable.

1-Octanol↗
PubMed2002

Theoretical and experimental exploration of the lipophilicity of zwitterionic drugs in the 1,2-dichloroethane/water system.

PURPOSE: This work examines the lipophilic behavior of various zwitterions and shows how distribution profiles in biphasic systems and ionic partition diagrams may improve our understanding of pH-absorption profiles of drugs. METHODS: The lipophilicity of various zwitterionic drugs was examined by potentiometry and cyclic voltammetry in the 1,2-dichloroethane/water system to study the intramolecular interactions and conformational effects affecting absorption and activity of zwitterions, as well as to draw their theoretical and experimental ionic partition diagrams. RESULTS: Different theoretical partition diagrams are reported according to the tautomeric constant of the zwitterion. Shifts of apparent PKa are obtained in the ionic partition diagrams of raclopride and eticlopride and compared to the deviations from pH-absorption profile described in the literature for lipophilic drugs. The physicochemical origin of these shifts is discussed. CONCLUSIONS: The comparison between pH-absorption profiles and ionic partition diagrams of zwitterions is shown here to be of value for a better mechanistic understanding of absorption processes, thus opening new perspectives in studying pH-absorption profiles of ionizable drugs.

Ethylene Dichlorides↗
PubMed2002

Quantitative structure-permeation relationships for solute transport across silicone membranes.

PURPOSE: The purpose of this work was to assess the molecular properties that influence solute permeation across siliconemembranes and to compare the results with transport across human skin. METHODS: The permeability coefficients (log Kp) of a series of model solutes across silicone membranes were determined from the analysis of simple transport experiments using a pseudosteady-state mathematical model of the diffusion process. Subsequently, structure permeation relationships were constructed and examined, focusing in particular on the difference between solute octanol/water and 1,2 dichloroethane/water partition coefficients (deltalog P(oct-dce)), which re ported upon H-bond donor activity, and the computationally derived molecular hydrogen-bonding potential. RESULTS: The hydrogen-bond donor acidity and the lipophilicity of the compounds examined greatly influenced their permeation across sil cone membranes. Furthermore, for a limited dataset, a significant correlation was identified between solute permeation across silicone membranes and that through human epidermis. CONCLUSION: The key molecular properties that control solute perme ation across silicone membranes have been identified. For the set of substituted phenols and other unrelated compounds examined here a similar structure-permeation relationship has been derived for their transport through human epidermis, suggesting application of the results to the prediction of flux across biological barriers.

Biological Transport↗